This is the first renewal application for this Program Project Grant, currently at 3.5 years of a 4 year grant. The focus has been and remains a study of the molecular and cellular pathways that regulate the balance of Th1 and Th2 cytokine patterns. It makes a particular effort to integrate specific signal pathways with important cellular questions. These studies make use of several in vivo models of infectious and autoimmune diseases as well as immune memory. It also examines an aspect of Th1/Th2 regulation that is less frequently considered, the cellular interactions that influence the Th1/Th2 balance once it is established; in this case by gamma/delta T cells. This Program Project also combines the expertise of two institutions, The University of Vermont (UVM) and the Trudeau Institute, two hours from UVM in Saranac Lake, NY. The UVM investigators (Drs. Ralph Budd, Mercedes Rincon, Sally Huber, Cory Teuscher) have expertise is cell signaling, immunogenetics, and viral immunology, whereas the Trudeau investigators (Drs. Susan Swain, Laura Haynes, and Markus Mohrs) have expertise in the study of immune memory and cytokine gene regulation, both of which are critical to our studies. The principal signal pathways studied in this Program Project converge on two important transcription factors for cytokine gene regulation, NFAT and NF-kB. IL-6 triggers IL-4 production in naive CD4+ -T cells via NFATc2 (Project 1), whereas gamma/delta T cells express high levels of FasL via NFAT which selectively kill Th2 cells in a Fas-dependent manner (Project 3). Similarly, c-FLIP (the death receptor inhibitor studied in Project 2) and the Histamine 1 Receptor (H1R, a susceptibility gene locus for EAE studied in Project 4) converge on the NF-kB pathway, c-FLIP signals NF-kappaB via RIP to costimulate T cells, and H1R connects to G-proteins and PKC theta to signal NF-kappaB. All four projects examine how these signal pathways and cell types influence the Th1/Th2 environment. In addition, Projects 1 and 2 also examine how the c-FLIP/NF-kappaB and IL-6/NFAT pathways influence the transition from effector Th1/Th2 to memory CD4+ T cell. Progress during the current funding period has been substantial (over 30 publications), 8 of which are multi-authored among the Program investigators, the renewal application includes two new investigators, Dr. Cory Teuscher, a leading immunogeneticist, and Dr. Markus Mohrs, with expertise in cytokine gene regulation.